Faron-Górecka Agata, Górecki Andrzej, Kuśmider Maciej, Wasylewski Zygmunt, Dziedzicka-Wasylewska Marta
Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Eur Neuropsychopharmacol. 2008 Sep;18(9):682-91. doi: 10.1016/j.euroneuro.2008.05.001. Epub 2008 Jun 11.
Clozapine is effective although still not perfect drug used to treat schizophrenia. The precise mechanism of its action is not known. Here we show that there are two binding sites for clozapine at the dopamine D1 and D2 receptors, and the affinity of D1R strongly depended on whether the receptor was present alone or together with D2R (or its genetic variant D2Ser311Cys) in the cell membrane, pointing to the role of receptor hetero-dimerization in the observed phenomenon. The use of fluorescence resonance energy transfer (FRET) technology, observed via fluorescence lifetime microscopy of the single cell, indicated that low concentration of clozapine (10(-9) M), sufficient to saturate the high affinity site, uncoupled the D1R-D2R hetero-dimers. Therefore it has been concluded that clozapine might antagonize the effect of concomitant stimulation of both dopamine receptors, which has been shown previously to enhance the formation of hetero-dimers and to stimulate the calcium signaling pathway.
氯氮平是一种用于治疗精神分裂症的有效药物，尽管仍不完美。其确切作用机制尚不清楚。在此我们表明，氯氮平在多巴胺D1和D2受体上有两个结合位点，并且D1R的亲和力强烈依赖于受体是单独存在于细胞膜中还是与D2R（或其基因变体D2Ser311Cys）一起存在，这表明受体异二聚化在观察到的现象中起作用。通过单细胞荧光寿命显微镜观察使用荧光共振能量转移（FRET）技术表明，低浓度的氯氮平（10^(-9) M）足以饱和高亲和力位点，使D1R-D2R异二聚体解偶联。因此得出结论，氯氮平可能拮抗多巴胺两种受体同时刺激的效应，先前已表明这种效应会增强异二聚体的形成并刺激钙信号通路。
